Epidemiologic studies support a genetic basis for susceptibility to human SLE. New information from genetically defined murine models of systemic lupus also support the view of a complex, polygenic disease with a threshold liability for inheritance. These studies in "lupus-like" mice suggest that different genes may control different aspects of the "lupus" phenotypes. Most importantly, these studies coupled with the rapid advances in knowledge available through the human genome project, underscore the feasibility of using the tools of modern genetics in defining human disease susceptibility and severity. The approach to the genetics of human SLE requires a multi-disciplinary, team effort. Within this SCOR, we have assembled a unique and exceptionally strong multi-disciplinary team which leverages both fundamental and clinical investigations and SLE at the host institution and at the partner institutions. Our team expertise includes mastery of the theory and techniques of modern genetic mapping (linkage), full appreciation of the SLE clinical phenotypes and the proven ability to recruit and maintain cohorts of SLE patients (sib-pairs, multiplex families, simplex families and longitudinal cohorts). Uniting this expertise is a deep appreciation for the pathophysiological processes in SLE in order to facilitate the selection of candidate genes and to translate findings into meaningful, mechanism-based clinical intervention. Through our team effort, we have an unprecedented power to accelerate the pace of discovery, to replicate and confirm regions of linkage, to narrow regions of interest, to pursue the structure and biology of candidate genes, and to test the relevance of these discoveries to clinical phenotype in a very large, meticulously studied cohort of SLE patients. Our efforts will advance our understanding of SLE and leverage both the application and current therapy and the development of new, mechanism based therapies.